This application is a continuation of copending prior filed international application designating the United States of America Serial No. PCT/IB00/01446 filed Oct. 6, 2000 (Attorney Docket No. PC10352), the benefit of the filing date of which is claimed, and which is incorporated herein by reference in its entirety; and corresponds to copending prior filed foreign application Great Britain Serial No. 9924361.0 filed Oct. 14, 1999 (Attorney Docket No. PC10352), the benefit of the filing date of which is claimed, and which is incorporated herein by reference in its entirety.
This invention relates to purine derivatives. More particularly, this invention relates to N-[(purin-2-yl)methyl]sulphonamide derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives.
These derivatives are selective, functional agonists of the human adenosine A2a receptor and may be used as anti-inflammatory agents in the treatment of, inter alia, diseases of the respiratory tract.
Adenosine is a ubiquitous molecule having a central role in mammalian intermediary metabolism. Independently, adenosine acts on multiple surface receptors to produce a variety of responses. Adenosine receptor classification has revealed the presence of at least four subtypes: A1, A2a, A2b and A3. Stimulation of adenosine A2 receptors on the surface of human neutrophils has been reported to potently inhibit a range of neutrophil functions. Activated neutrophils can damage lung tissue by release of reactive oxygen species, for example, superoxide anion radicals (O2xe2x88x92.), and granule products, for example, human neutrophil elastase (HNE), amongst other inflammatory mediators. In addition, activated neutrophils perform both de novo synthesis and release of arachidonate products such as leukotriene B4 (LTB4). LTB4 is a potent chemo-attractant that recruits additional neutrophils to the inflammatory focus, whereas released O2xe2x88x92.and HNE adversely affect the pulmonary extracellular matrix. The A2 receptor subtype mediating many of these responses (O2xe2x88x92. and LTB4/HNE release and cell adhesion) is established as A2a. The A2 subtype (A2a or A2b) mediating the other effects remains to be established.
Selective agonist activity at the A2a receptor is considered to offer greater therapeutic benefit than the use of non-selective adenosine receptor agonists because interaction with other subtypes is associated with detrimental effects in the lung in animal models and human tissue studies. For example, asthmatics, but not non-asthmatics, bronchoconstrict when challenged with inhaled adenosine. This response is at least in part due to the activation of the A1 receptor subtype. Activation of A1 receptors also promotes neutrophil chemotaxis and adherence to endothelial cells, thus promoting lung injury. Furthermore, many patients with respiratory disease will be co-prescribed xcex22-agonists, and negative interaction has been shown in animal studies between isoprenaline and adenosine receptors negatively coupled to adenylate cyclase. Degranulation of human mast cells is promoted by activation of adenosine A2b receptors, thus selectivity over the A2b receptor is also advantageous.
We have now surprisingly found the present purine derivatives inhibit neutrophil function and are selective agonists of the adenosine A2a receptor. They may also have antagonist activity at the adenosine A3 receptor. The present compounds may be used to treat any disease for which an adenosine A2a receptor agonist is indicated. They can be used to treat a disease where leukocyte (e.g. neutrophil, eosinophil, basophil, lymphocyte, macrophage)xe2x80x94induced tissue damage is implicated. They are useful as anti-inflammatory agents in the treatment of diseases of the respiratory tract such as adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis. The present compounds may also be used in the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, dermatitis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing.
Accordingly, the present invention provides a compound of the formula: 
or a pharmaceutically acceptable salt or solvate thereof,
wherein R1 is hydrogen or C1-C6 alkyl optionally substituted by 1 or 2 substituents each independently selected from phenyl and naphthyl, said phenyl and naphthyl being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, halo or cyano;
A is a bond or C1-C3 alkylene;
R2 is (i) hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or naphthyl, said C3-C7 cycloalkyl, phenyl or naphthyl being optionally substituted by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3N-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, C2-C5 alkanoyl, halo, xe2x80x94OR3, cyano, xe2x80x94COOR3, C3-C7 cycloalkyl, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94CONR3R3xe2x80x94NR3COR or xe2x80x94NR3SO2R4, with the proviso that R2 is not hydrogen when A is a bond,
xe2x80x83or (ii) when A is C2-C3 alkylene, xe2x80x94NR8R9, xe2x80x94OR3, xe2x80x94COOR3, xe2x80x94OCOR4, xe2x80x94SO2R4, xe2x80x94CN, xe2x80x94SO2NR3R3, xe2x80x94NR3COR4 or xe2x80x94CONR3R3,
xe2x80x83or (iii) a C-linked, 4 to 11 membered, mono or bicyclic heterocycle having either from 1 to 4 ring nitrogen atom(s) or 1 or 2 nitrogen and 1 oxygen or 1 sulphur ring atoms, optionally C-substituted by oxo, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3N-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C1-C6)-alkoxy, fluoro-(C2-C5)-alkanoyl, halo, cyano, xe2x80x94OR5, R6, xe2x80x94COR5, xe2x80x94NR5R5, xe2x80x94COOR5, xe2x80x94S(O)mR6, xe2x80x94SO2NR5R5, xe2x80x94CONR5R5, xe2x80x94NR5SO2R6 or xe2x80x94NR5COR6 and optionally N-substitute by C1-C6 alkoxy-(C1C6)-alkyl, R3R3N-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, fluoro-(C2-C5)-alkanoyl, R6, xe2x80x94COR5, xe2x80x94COOR5, xe2x80x94S(O)mR6, xe2x80x94SO2NR5R5 or xe2x80x94CONR5R5;
R3 is H, C1-C6 alkyl, C3-C7 cycloalkyl or phenyl;
R4 is C1-C6 alkyl, C3-C7 cycloalkyl or phenyl;
R5 is H, C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
R6 is C1-C6 alkyl, C3-C7 cycloalkyl, phenyl, naphthyl or het;
m is 0, 1 or 2;
xe2x80x9chetxe2x80x9d, used in the definitions of R5and R6, means C-linked pyrrolyl imidazolyl triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl or quinoxalinyl, each optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, cyano or halo;
R7 is methyl, ethyl or cyclopropylmethyl; and
either, R8 and R9, taken together with the nitrogen atom to which they are attached represent azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperidinyl, homopiperazinyl or tetrahydroisoquinolinyl, each being optionally substituted on a ring carbon atom by C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, C1-C6 alkoxy-(C1-C6)-alkyl, R3R3N-(C1-C6)-alkyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR3R3, xe2x80x94COOR3 or C2-C5 alkanoyl, and optionally substituted on a ring carbon atom not adjacent to a ring nitrogen atom by fluoro-(C1-C6)-alkoxy, halo, xe2x80x94OR3, cyano, xe2x80x94S(O)mR4, xe2x80x94NR3R3, xe2x80x94SO2NR3R3, xe2x80x94NR3COR4 or xe2x80x94NR3SO2R4, and said piperazin-1-yl and homopiperazin-1-yl being optionally substituted on the ring nitrogen atom not attached to A by C1-C6 alkyl, phenyl, C1-C6 alkoxy-(C2-C6)-alkyl, R3R3N-(C2-C6)-alkyl, fluoro-(C1-C6)-alkyl, C2-C5 alkanoyl, xe2x80x94COOR4, C3-C8 cycloalkyl, xe2x80x94SO2R4, xe2x80x94SO2NR3R3 or xe2x80x94CONR3R3,
xe2x80x83or, R8 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl or benzyl and R9 is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl, fluoro-(C1-C6)-alkyl, xe2x80x94CONR3R3, xe2x80x94COOR4, C2-C5 alkanoyl or xe2x80x94SO2NR3R3.
In the above definitions, halo means fluoro, chloro, bromo or iodo and alkyl, alkylene, alkanoyl and alkoxy groups containing the requisite number of carbon atoms can be unbranched or branched chain. The heterocycle as defined in R2 part (iii), above may be aromatic or fully or partially saturated. The expression xe2x80x98C-linkedxe2x80x99 used in the definition of R2 and xe2x80x9chetxe2x80x9d means that the group is linked to the adjacent atom by a ring carbon atom. Examples of alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl and t-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and t-butoxy. Examples of alkylene include methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene and 1,2-propylene. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable salts of the compounds of the formula (I) include the acid addition and the base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts and examples are the hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, succinate, saccharate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts.
Suitable base salts are formed from bases which form non-toxic salts and examples are the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts.
For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1-19.
The pharmaceutically acceptable solvates of the compounds of the formula (I) include the hydrates thereof.
Also included within the present scope of the compounds of the formula (I) are polymorphs thereof.
A compound of the formula (I) may contain one or more additional asymmetric carbon atoms and therefore exist in two or more stereoisomeric forms. The present invention includes the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof.
Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
Preferably, R1 is C1-C6 alkyl optionally substituted by 1 or 2 phenyl group(s), said phenyl group(s) being optionally substituted by C1-C6 alkoxy.
Preferably, R1 is C1-C6 alkyl substituted by 1 or 2 phenyl group(s), said phenyl group(s) being optionally substituted by C1-C6 alkoxy.
Preferably, R1 is C1-C4 alkyl substituted by 1 or 2 phenyl group(s), said phenyl group(s) being optionally substituted by C1-C4 alkoxy.
Preferably, R1 is C1-C2 alkyl substituted by 1 or 2 phenyl group(s), said phenyl group(s) being optionally substituted by C1-C4 alkoxy.
Preferably, R1 is diphenylethyl or (methoxyphenyl)methyl.
Preferably, R1 is 2,2-diphenylethyl or (4-methoxyphenyl)methyl.
Preferably, R1 is 2,2-diphenylethyl.
Preferably, A is a bond.
Preferably, A is C1-C3 alkylene.
Preferably, A is C2-C3 alkylene.
Preferably, A is C2 alkylene.
Preferably, A is xe2x80x94CH2CH2xe2x80x94.
Preferably, R2 is C1-C6 alkyl, phenyl, naphthyl or xe2x80x94NR8R9, said xe2x80x94NR8R9 preferably being piperidin-1-yl and said phenyl being optionally substituted by phenyl.
Preferably, R2 is C1-C4 alkyl, phenyl, naphthyl or piperidin-1-yl, said phenyl being optionally substituted by phenyl.
Preferably, R2 is methyl, n-propyl, isopropyl, 2-methylprop-1-yl, phenyl, naphthyl or piperidin-1-yl, said phenyl being optionally substituted by phenyl.
Preferably, R2 is methyl, n-propyl, isopropyl, 2-methylprop-1-yl, phenyl, 4-phenylphenyl, 1-naphthyl, 2-naphthyl or piperidin-1-yl.
Preferably, xe2x80x94Axe2x80x94R2 is methyl, n-propyl, isopropyl, 2-methylprop-1-yl, phenyl, 4-phenylphenyl, phenylmethyl, 1-naphthyl, 2-naphthyl or 2-(piperidin-1-yl)ethyl.
Preferably, R7 is ethyl.
Preferred examples of compounds of the formula (I) include those of the Examples section hereafter, including any pharmaceutically acceptable salts thereof.
All the compounds of the formula (1) can be prepared by conventional routes such as by the procedures described in the general methods presented below or by the specific methods described in the Examples section, or by similar methods thereto. The present invention also encompasses any one or more of these processes for preparing the compounds of formula (I), in addition to any novel intermediates used therein. In the general methods described, R1, R2, R7 and A are as previously defined unless otherwise stated.
All the compounds of the formula (I) can be prepared by deprotection of a compound of the formula 
wherein P1 and P2 represent suitable protecting groups which may be the same or different, or P1 and P2may optionally form part of the same protecting group. Examples of suitable protecting groups will be apparent to the skilled man [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. Preferred individual protecting groups are silyl (substituted with three groups selected independently from aryl and alkyl), alkanoyl and aroyl. A preferred protecting group where P1 and P2form part of the same protecting group is where P1 and P2 taken together are C1-C6 alkylene. Particularly preferred individual protecting groups are benzoyl and acetyl. Particularly preferred protecting groups where P1 and P2 form part of the same protecting group are where P1 and P2 taken together are dimethylmethylene. Examples of the conditions used to achieve the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are both benzoyl, the protecting groups may be removed by treating a solution of the compound of the formula (II) in a suitable solvent, such methanol, with a base such as potassium carbonate, typically at room temperature. In a typical procedure where P1 and P2 taken together are dimethylmethylene, the deprotection may be carried out in the presence of a suitable acid, e.g. an aqueous mineral acid such as hydrochloric acid. In some cases, depending on the nature of the protecting groups P1 and P2 and the available methods for their removal, it may be expedient not to isolate compounds of the formula (II) following a prior reaction step but to deprotect them in situ. In a typical case, where P1 and P2 taken together are dimethylmethylene, the compound of the formula (II) is deprotected in situ in a suitable solvent such as ethanol using hydrochloric acid at a temperature of from 20 to 100xc2x0 C.
The protecting groups P1 and P2 may be removed together in a single step or sequentially, in either order.
Compounds of the formula (II) may be prepared according to the route shown in Scheme I, wherein X is a leaving group, preferably chloro, and Ac is acetyl. 
Compounds of the formula (II) may be prepared by the reaction of a compound of the formula (III) with a silyl derivative of a compound of formula (IV) according to known methods. In a typical procedure, the compound of the formula (IV) is heated as a suspension in 1,1,1,3,3,3-hexamethylsilazane under a nitrogen atmosphere until a solution has been formed. The mixture is concentrated to dryness and a solution of the residue in a suitable solvent (e.g. acetonitrile) is treated with the compound of the formula (III) and trimethylsilyl trifluoromethanesulphonate to provide a compound of the formula (II). Compounds of the formula (IV) may be prepared by the hydrolysis of a compound of the formula (V). Typically, the compound of the formula (V) is dissolved in a suitable solvent such as ethanol and treated with an acid such as hydrochloric acid. The reaction may be performed at from 0 to 100xc2x0 C., preferably at from 20 to 50xc2x0 C. Compounds of the formula (V) may be prepared by the sulphonylation of a compound of the formula (VI) with a compound of the formula (VII). In a typical procedure, a solution of the compound of the formula (VI) in a suitable inert solvent such as dichloromethane is treated with the sulphonylating agent. An acid acceptor such as triethylamine may be optionally added. Compounds of the formula (VI) may be prepared by the reduction of a compound of formula (VIII). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, a solution of the compound of the formula (VIII) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as Pearimann""s catalyst and pressurised with hydrogen, preferably to 414 kPa (60 psi). Compounds of the formula (VIII) may be prepared by reacting a compound of the formula (IX) with a source of cyanide anion such as potassium cyanide. The reaction is typically carried out in a solvent such as N,N-dimethylformamide at an elevated temperature. Compounds of the formula (IX) may be prepared by the oxidation of a compound of the formula (X). In a typical procedure, an aqueous solution of potassium peroxymonosulphate is added to a solution of the compound of the formula (X) and sodium hydrogencarbonate in a suitable solvent, such as a mixture of water and acetone. Compounds of the formula (X) may be prepared by the displacement of chloride in a compound of the formula (XI) with thiomethoxide. Typically, the reaction is carried out in a polar solvent such as N,N-dimethylformamide, at elevated temperatures and under a blanket of nitrogen. Thiomethoxide may be used in the form of an alkali metal salt such as sodium thiomethoxide. Compounds of the formula (XI) may be prepared by the reaction of a compound of the formula (XII) with an appropriate primary amine. Typically, a solution of the dichloropurine (XII) in a suitable solvent such as isopropyl alcohol is treated with such an amine and heated, preferably under reflux. An acid acceptor such as N-ethylxe2x80x94N-isopropyl-2-propanamine may optionally be added. Compound (XII) may be prepared by reaction of 2,6-dichloro-9H-purine (XIII) with 2,3-dihydropyran in a suitable solvent such as ethyl acetate and in the presence of an acid catalyst such as 4-toluenesulphonic acid, usually at an elevated temperature.
Compounds of the formula (II) may also be prepared by the reaction of an amine of the formula (XIV) with a sulphonylating agent of the formula (VII) as shown in Scheme 2, wherein X is a leaving group, preferably chloro, Ac is acetyl and P1 and P2 are as defined above. 
In a typical procedure, a solution of the compound of the formula (XIV) in a suitable inert solvent such as dichloromethane is treated with the compound of the formula (VII). An acid acceptor such as triethylamine may optionally be added. Compounds of formula (XIV), where P1 and P2 taken together are dimethylmethylene, for example, may be prepared by reduction of a compound of formula (XV). The reduction may be carried out with any suitable hydride reducing agent or by hydrogenation. In a typical procedure, where P1 and P2 taken together are dimethylmethylene, a solution of the compound of formula (XV) in a suitable solvent such as ethanol is saturated with ammonia gas, treated with an appropriate hydrogenation catalyst such as 5% w/w palladium on charcoal and pressurised with hydrogen, preferably to about 1034 kPa (150 psi). Compounds of the formula (XV) may be prepared by the reaction of a compound of the formula (III) with a compound of formula (XVI) according to known methods. In a typical procedure, a mixture of the compound of the formula (XVI), the compound of the formula (III) and iodine is heated at about 150xc2x0 C. under reduced pressure. With regard to the conditions to be employed in later steps, it may be appropriate to change the protecting groups P1 and P2 in compounds of the formula (XV). Alternative, suitable protecting groups are well-known to the skilled person [e.g. xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical case, if P1 and P2 in a compound of the formula (XV) are both benzoyl, then these protecting groups may be vulnerable to the reducing conditions employed in the next step. In this case, a solution of the compound of the formula (XV) where P1 and P2 are both benzoyl in a suitable solvent such as ethanol may be saturated with ammonia to give a compound of the formula (XV) wherein P1 and P2 are replaced by H which may be subsequently reprotected with more appropriate functionality. For instance, the compound of the formula (XV) wherein P1 and P2 are replaced by H may be dissolved in acetone and the resulting solution treated with 2,2-dimethoxypropane and 10-camphorsulphonic acid to give a compound of the formula (XV) wherein P1 and P2 taken together are dimethylmethylene. Compounds of formula (XVI) may be prepared by the hydrolysis of a compound of the formula (VIII). Typically, the compound of the formula (VII) is dissolved in a suitable solvent such as ethanol and treated with an acid such as hydrochloric acid.
Compounds of the formula (III), used in Schemes 1 and 2, may be prepared as shown in Scheme 3 wherein Ac is acetyl and P1 and P2 are as defined above. 
Compounds of the formula (III) may be prepared by the treatment of a compound of the formula (XVII) with a mixture of acetic acid, acetic anhydride and a strong acid such as hydrochloric acid, preferably with cooling (typically to xe2x88x9210xc2x0 C.). Compounds of the formula (XVII) may be prepared from an acid of the formula (XVIII) by activation of the acid as, for example, an acid chloride and treatment of this activated intermediate with an appropriate primary amine. In a typical procedure, a compound of the formula (XVIII) is dissolved in a suitable inert solvent (e.g. dichloromethane) and treated with oxalyl chloride and a catalytic amount of N,N-dimethylformamide. After removal of excess solvent and reagent by evaporation under reduced pressure, the residue is dissolved in a suitable solvent, such as anhydrous dichloromethane and treated with the appropriate primary amine. With regard to the conditions employed in later steps, it may be appropriate to switch the protecting groups P1 and P2 in compounds of the formula (XVII). Alternative, suitable protecting groups are well-known to the skilled person [e.g. xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical case, a solution of the compound of the formula (XVII) wherein Pt and P2 taken together are dimethylmethylene in a suitable solvent such as methanol may treated with an acid such as pyridinium para-toluenesulphonate to give a compound of the formula (XVII) wherein P1 and P2 are both replaced by H which may be subsequently reprotected with other functionality. For instance, the compound of the formula (XVII) wherein P1 and P2 are both replaced by H may be dissolved in a suitable solvent such as dichloromethane and the resulting solution may be treated with an acid acceptor, such as pyridine and benzoyl chloride to give a compound of the formula (XVII) wherein P1 and P2 are each benzoyl. Compounds of the formula (XVIII) are known in the art (see for example in J. Amer. Chem. Soc., 1958, 80, 5168).
All the compounds of the formula (I) may also be prepared by the sulphonylation of a compound of the formula (XIX) with a compound of the formula (VII) as shown in Scheme 4 wherein X is a leaving group, preferably Cl and P1 and P2 are as previously defined. 
In a typical procedure, a solution of the compound of the formula (XIX) in a suitable inert solvent such as dichloromethane is treated with the sulphonylating agent of the formula (VII). An acid acceptor such as triethylamine may optionally be added. Compounds of the formula (XIX) may be prepared by the deprotection of a compound of the formula (XIV). Examples of the conditions used to achieve the deprotection are well known in the art [see for instance xe2x80x98Protecting Groups in Organic Synthesis (Second Edition)xe2x80x99, Theodora W. Green and Peter G. M. Wuts, John Wiley and Sons, 1991]. In a typical procedure, where P1 and P2 are both benzoyl, the protecting groups may be removed by treating a solution of the compound of the formula (II) in a suitable solvent, such methanol, with a base such as potassium carbonate, typically at room temperature. In a typical procedure where P1 and P2 taken together are dimethylmethylene, the deprotection may be carried out in the presence of a suitable acid, e.g. in aqueous mineral acid such as hydrochloric acid. Compounds of the formula (I) in which A is xe2x80x94CH2CH2xe2x80x94 and R2 is xe2x80x94NR8R9 may also be prepared by the reaction of a compound of the formula (XIX) with 2-chloroethanesulfonyl chloride to give an intermediate of the formula 
The intermediate of the formula (XX) is then treated with a compound of the formula
R8R9NHxe2x80x83xe2x80x83(XXI)
in which R8 and R9 are as defined above, to give a compound of the formula (I). The two steps may be carried out with or without isolation of the intermediate of the formula (XX). In a typical procedure, where the intermediate of the formula (XX) is not isolated, a solution of the compound of the formula (XIX) in a suitable solvent, such as acetonitrile, is treated with chioroethanesulfonyl chloride and a base, such as pyridine. When a substantially complete reaction has taken place (as judged by thin layer chromatography) a compound of the formula (XXI) is added and the reaction mixture is heated, preferably under reflux. Compounds of the formula (XXI) are either commercially available or easily prepared by techniques well known to the skilled person. Compounds of the formula (I) may also be interconverted using conventional functional group interconversion techniques. All of the reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions as well as procedures for isolating the desired products will be well-known to persons skilled in the art with reference to literature precedents and the Examples and Preparations sections below. pharmaceutically acceptable salt of a compound of the formula (I) may be readily prepared by mixing together solutions of a compound of the formula (I) and the desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
The anti-inflammatory properties of the compounds of the formula (I) are demonstrated by their ability to inhibit neutrophil function which indicates A2a receptor agonist activity. This is evaluated by determining the compound profile in an assay where superoxide production was measured from neutrophils activated by fMLP. Neutrophils were isolated from human peripheral blood using dextran sedimentation followed by centrifugation through Ficoll-Hypaque solution. Any contaminating erythrocytes in the granulocyte pellet were removed by lysis with ice-cold distilled water. Superoxide production from the neutrophils was induced by fMLP in the presence of a priming concentration of cytochalasin B. Adenosine deaminase was included in the assay to remove any endogenously produced adenosine that might suppress superoxide production. The effect of the compound on the fMLP-induced response was monitored colorometrically from the reduction of cytochrome C within the assay buffer. The potency of the compounds was assessed by the concentration giving 50% inhibition (IC50) compared to the control response to fMLP.
The compounds of the formula (I) can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds of the formula (I) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, sustained-, pulsed- or controlled-release applications.
Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or a high molecular weight polyethylene glycol. For aqueous suspensions and/or elixirs, the compounds of the formula (I) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.
The compounds of the formula (I) can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intrastemally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques. They are best used in the form of a sterIIe aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art. For oral and parenteral administration to human patients, the daily dosage level of the compounds of the formula (I) will usually be from 0.01 to 100 mg/kg, preferably from 0.1 to 100 mg/kg (in single or divided doses).
Thus tablets or capsules of the compound of the formula (I) may contain from 5 to 500 mg of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
The compounds of formula (I) can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, with or without the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A [trade mark]) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA [trade mark]), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the formula (I) and a suitable powder base such as lactose or starch.
Aerosol or dry powder formulations are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d contains from 20 to 4000 xcexcg of a compound of the formula (I) for delivery to the patient. The overall daily dose with an aerosol will be in the range of from 20 xcexcg to 20 mg which may be administered in a single dose or, more usually, in divided doses throughout the day.
Alternatively, the compounds of the formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of the formula (I) may also be transdermally administered, for example, by the use of a skin patch.
For application topically to the skin, the compounds of the formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
The compounds of the formula (I) may also be used in combination with a cyclodextrin. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. Formation of a drug-cyclodextrin complex may modify the solubility, dissolution rate, bioavailability and/or stability property of a drug molecule. Drug-cyclodextrin complexes are generally useful for most dosage forms and administration routes. As an alternative to direct complexation with the drug the cyclodextrin may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. Alpha-, beta- and gamma-cyclodextrins are most commonly used and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.
It is to be appreciated that all references herein to treatment include curative, palliative and prophylactic treatment.
Thus the invention provides:
(i) a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(ii) a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof;
(iii) a pharmaceutical composition including a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable excipient, diluent or carrier;
(iv) a compound of the formula (I) or a pharmaceutically acceptable salt, solvate or composition thereof, for use as a medicament;
(v) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament to treat a disease for which a A2a receptor agonist is indicated;
(vi) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of an anti-inflammatory agent;
(vii) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of a respiratory disease;
(viii) use as in (vii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(ix) the use of a compound of the formula (I) or of a pharmaceutically acceptable salt, solvate or composition thereof, for the manufacture of a medicament for the treatment of septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing;
(x) a method of treatment of a mammal, including a human being, to treat a disease for which a A2a receptor agonist is indicated including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xi) a method of treatment of a mammal, including a human being, to treat an inflammatory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xii) a method of treatment of a mammal, including a human being, to treat a respiratory disease including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof;
(xiii) a method as in (xii) where the disease is selected from the group consisting of adult respiratory distress syndrome (ARDS), bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, bronchiectasis, chronic sinusitis and rhinitis;
(xiv) a method of treatment of a mammal, including a human being, to treat septic shock, male erectile dysfunction, hypertension, stroke, epilepsy, cerebral ischaemia, peripheral vascular disease, post-ischaemic reperfusion injury, diabetes, rheumatoid arthritis, multiple sclerosis, psoriasis, allergic dermatitis, eczema, ulcerative colitis, Crohns disease, inflammatory bowel disease, Heliobacter pylori-gastritis, non-Heliobacter pylori gastritis, non-steroidal anti-inflammatory drug-induced damage to the gastro-intestinal tract or a psychotic disorder, or for wound healing, including treating said mammal with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt, solvate or composition thereof; and
(xv) certain novel intermediates disclosed herein.